Vol. 113 No. 1 January 2012

ORAL MEDICINE

Risk factors for osteoradionecrosis after head and neck radiation:a systematic reviewSyed Nabil, DDS, MDS,a and Nabil Samman, FRCS, FDSRCSb

The National University of Malaysia, Kuala Lampur, Malaysia; and University of Hong Kong, Hong Kong

Objective. This systematic review aimed to answer the clinical question, “What is the current risk of developingosteoradionecrosis of the jaws among irradiated head and neck cancer patients?”Study Design. A systematic review of published English-language randomized controlled trials on the outcome of radiation therapywas performed via Medline and Embase databases. Data on osteoradionecrosis/bone toxicity were collected and analyzed.Results. Twenty-two articles reporting on a total of 5,742 patients were selected for final review based on strict eligibilitycriteria. An estimated 2% of the head and neck–irradiated patients are at risk of developing osteoradionecrosis. Patientsreceiving adjunctive radiotherapy, accelerated fractionation without dose reduction, and chemoradiotherapy show noincrease in osteoradionecrosis risk. Accelerated fractionation with dose reduction is associated with a reduced risk, whereashyperfractionation shows elevated risk of developing osteoradionecrosis.Conclusions. The risk of developing osteoradionecrosis among the irradiated head and neck cancer patient has significantly

declined in recent years. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:54-69)

Radiotherapy (RT) alone or in combination with sur-gery is an established form of therapy for the treatment orpalliation of cancer patients. This treatment modality,however, has significant limitations in the form of acuteand late toxicity. Acute side effects, such as moist des-quamation, skin erythema, loss of taste, and especiallymucositis, are often debilitating but resolve with time.1

Late toxicity, such as radiation caries, trismus, xerostomia,myelitis, skin fibrosis, and osteoradionecrosis (ORN),however, can be more problematic, because they may bea lifelong problem for cancer survivors.1-3 Along withtumor recurrence or development of a second malignancy,ORN of the jaws is a most dreaded complication amongsurvivors of head and neck cancer.

In recent years, new advances in RT have been made,and there is increasing interest in combining chemother-apeutic (CT) agents with irradiation in an effort to achievebetter locoregional disease control and higher survivalrates.4,5 The delivery of RT has also changed with theadvent of new technologies, such as 3D conformal radio-therapy (3D-CRT) and intensity-modulated radiotherapy(IMRT), with the purpose of reducing the radiation expo-sure of normal regional tissues.6-9 The rate and total dose

aLecturer, Oral and Maxillofacial Surgery, Faculty of Dentistry,National University of Malaysia.bProfessor, Oral and Maxillofacial Surgery, Faculty of Dentistry,University of Hong Kong.Received for publication Dec. 15, 2010; returned for revision Jul. 14,2011; accepted for publication Jul. 23, 2011.© 2012 Elsevier Inc. All rights reserved.2212-4403/$ - see front matter

doi:10.1016/j.tripleo.2011.07.042

54

delivery have also been extensively tested to assess theeffectiveness of different fractionation regimes and lengthof treatment in controlling disease and their effect on acuteand late toxicity.10,11

Historically, the incidence of ORN in the head andneck–irradiated population was estimated to be 4.74%-37.5% (Table I).12-20 With the current advances inradiation technologies and the introduction of dentalcare protocols for head and neck cancer patients, thecurrent risk of developing ORN is assumed to havedeclined but is in fact unknown. Moreover, the differ-ences in the incidence of ORN associated with differentradiation regimens, different fractionations, and differ-ent delivery methods are unclear. The effect of com-bining CT with radiotherapy on ORN risk also is notknown. The present systematic review aims to clarifythe effects of different radiation protocols on the risk ofdeveloping ORN of the jaws in the irradiated head andneck cancer population.

MATERIALS AND METHODSObjectiveWith the aim of answering the clinical question, “Whatis the current risk of developing ORN of the jawsamong irradiated head and neck cancer patients?,” asystematic literature search was performed to providethe best and most valid answer.

Study identificationAn electronic search was performed through Medlineand Embase using the combination of “head and neck

cancer,” “radiotherapy,” “radiotherapy late toxicity,”

OOOO ORIGINAL ARTICLEVolume 113, Number 1 Nabil and Samman 55

and “osteoradionecrosis” as key words to identify rel-evant articles (Figure 1).

Study selectionThe title and abstract of all articles retrieved by theelectronic search were screened. For articles reportingthe outcome of RT treatment for head and neck canceror for those with insufficient data in the title and ab-stract to make a clear decision about, the full text of thearticles were obtained. These articles were then evalu-ated, and articles meeting the inclusion criteria de-scribed in Table II were accepted for further assess-ment. Articles meeting the inclusion criteria were thenassessed further using predefined eligibility criteria fortheir inclusion in the final review. Studies rejected atthe eligibility assessment stage were recorded and thereasons for exclusion noted.

Type of studyOnly randomized controlled trials (RCTs) involvingRT on head and neck cancer patients with a minimumsample size of 20 patients per arm were considered. Aminimum of 20 patients is needed to give at least 1 caseof ORN based on the 4.74% ORN incidence rate re-ported by Withers et al.19 (Table I). A smaller samplesize could result in no ORN occurrence, which wouldmake it impossible to compare the difference in the riskof developing ORN between different treatment arms.Articles also had to have reported late bone toxicity/ORN. Other restrictions were English language only,publication date after 1995, and study on humans.

Participants. Consecutive groups of adult patientswho had radiation to the head and neck region exclud-ing lymphoma, esophageal, thyroid, and tracheal tu-mors were eligible. Subjects who were reirradiatedwere excluded. Palliative radiation was excluded, ow-ing to the expectation of a limited follow-up periodrelative to poor prognosis.

Intervention. Any RT regimes performed as a cura-tive or adjunctive therapy with surgery in the manage-ment of head and neck cancer were included.

Outcome measures. The primary outcome measure

Table I. Previously reported osteoradionecrosis (ORNAuthor Year Period

Watson and Scarborough12 1938 1930-1937MacCombe13 1962 1952-1959Grant and Fletcher14 1966 1954-1962Bedwinek et al.15 1976 1966-1971Daly et al.16 1972 1966-1971Murray et al.17 1980 1966-1975Morrish et al.18 1981 1971-1977Withers et al.19 1995 1976-1985Reuther et al.20 2003 1969-1999

was the occurrence of ORN after irradiation to the head

and neck region. ORN can be reported as present (yes/no) or as the presence of bone toxicity according to theRadiation Therapy Oncology Group/European Organi-sation for Research and Treatment of Cancer Late Ra-diation Morbidity Scoring Schema (RTOG/EORTC),1

Late Effects of Normal Tissue/Somatic Objective Man-agement Analytic (LENT/SOMA),3 or the NationalCancer Institute Common Toxicity Criteria (NCI-CTC).2 In articles reporting bone toxicity, RTOG/EORTC and LENT/SOMA grade/score 3 or 4 bonetoxicity and grade �1 for osteonecrosis in NTC-CTCwere considered to be ORN for the purpose of thisreview. Other outcomes examined were ORN risk indifferent tumor locations, the use of chemoradiotherapy(CRT), adjunctive or curative therapy, RT deliverytechniques, altered fractionation, ORN location withinthe jaws, and the reporting of dental evaluations.

Eligibility assessmentArticles meeting all of the following criteria were ac-cepted for the final review:

1. Actual number of cases of bone toxicity/bone ne-crosis/ORN reported.

2. Treatment regimen uniform within each arm.3. Original data (no secondary analysis).4. Reported follow-up of �5 years or median/mean

follow-up of surviving patients �3 years.5. Patient recruitment beginning from 1985 onward.

Data collectionThe data were collected in Microsoft Excel table form bythe first reviewer. The second reviewer reevaluated thecompleted table to ensure that there were no irregularitiesor missing data during the data extraction process.

RESULTSThe electronic database search was last updated in June2010. After title and/or abstract screening, 201 articlesappeared to be relevant for this review. Full text eval-uation of these 201 articles concluded that 53 articlesmet all of the inclusion criteria. After eligibility assess-

enceNo. of patients No. of ORN Percentage

1,819 235 12.9%251 93 37.1%176 66 37.5%381 54 14.2%304 66 21.7%653 138 21.1%100 22 22.0%676 32 4.7%830 68 8.2%

) incid

ment, 31 articles did not meet �1 of the validity crite-

the P

ORAL MEDICINE OOOO56 Nabil and Samman January 2012

ria. Reasons for exclusion are presented in Table III. Atotal of 22 articles were accepted for data extraction andanalysis.10,21-41 The flow chart of the systematic articleselection and evaluation is illustrated in Figure 1.

Primary outcomeBased on 22 RCTs, a total of 117 cases of ORN from

Figure 1. Flow diagram for study selection (as adapted from

among 5,742 irradiated head and neck cancer patients

were recorded, giving an incidence rate of 2% in theperiod between 1985 and 2010 (Table IV).

Risk of ORN for different tumor locationsAmong the 22 selected articles, 18 articles reported theoutcome of RT treatment within the region of the “headand neck cancer” (larynx, oral cavity, oropharynx, hy-

RISMA statement132).

popharynx) without subdividing to a more specific tu-

OOOO ORIGINAL ARTICLEVolume 113, Number 1 Nabil and Samman 57

mor location. One article reported the outcome of RT in“nasopharyngeal carcinoma,” and the remaining 3 re-ported on a subset of “head and neck cancer” (2 oro-pharynx and 1 tongue carcinoma). No selected articlesreported the outcome of RT treatment in the sinonasalregion (Table V). Among the 18 articles reportingoutcome of treatment on “head and neck cancer” pa-tients, none reported the relation of ORN/bone toxicitywith the subset location (larynx, oral cavity, orophar-ynx, hypopharynx).

Risk of developing ORN when CT agentswere usedOverall, 10 articles compared the outcome of RT aloneto that of CRT. Five articles reported higher incidenceof ORN when CRT was used,26,28,30,31,37 3 when RTalone was used,22,29,38 whereas 2 articles reported nodifference (Table VI).25,32

Risk of developing ORN in curative RT oradjunctive RT with surgeryOne article reporting the outcome of RT in nasopha-ryngeal carcinoma was excluded from the present anal-ysis to ensure homogeneity.33 When curative-intent RTtreatment was compared with adjunctive RT treatmentafter surgery, similar risk of developing ORN was seen(Table V).

Incidence with different delivery techniquesThere were no RCTs selected for this review that com-pared different radiation delivery techniques, such asconventional external-beam radiotherapy (EBRT),IMRT, 3D-CRT, or brachytherapy. One article com-pared high dose rate (HDR) with low dose rate (LDR)brachytherapy and reported higher incidence withHDR.35 Sixteen articles reported a comparison of dif-ferent treatment regimen with the use EBRT in botharms. Six articles failed to report clearly the deliverytechnique used22,26,27,30,34,40 and none of the articlesselected used IMRT or 3D-CRT. Results are shown in

Table II. Criteria for inclusion of articles in the finaleligibility assessment phaseRandomized controlled trial comparing outcome of different

radiotherapy treatment regimesPatients who had undergone radiotherapy in head and neck region

(excluding lymphoma, esophageal, thyroid, and tracheal tumors)Reporting the late bone toxicity/bone necrosis/osteoradionecrosisSample size �20 in each armExcluding reirradiationExcluding palliative treatmentHuman subjectsAdult subjects

Table V.

Difference in risk with different dose rates andtreatment time (conventional, accelerated,hyperfractionated)Altered fractionation was compared with conventionalfractionation in 7 articles and the results are shown inTable VII. Further subdivision to different categorieswas performed according to an earlier meta-analysis.11

When hyperfractionation was compared with conven-tional fractionation, both trials showed higher risk inthe intervention group.23,36 Two out of 5 articles com-paring accelerated fractionation without dose reductionto conventional fractionation showed an increased riskfor the intervention group,21,24 2 others showed a re-duced risk,34,36 and 1 showed no difference.25 Whenthe radiation dose was reduced and accelerated, the riskof developing ORN was reduced.10

Risk for the mandible and maxillaThe location of ORN was reported in only 7 of the 22articles (Table V). Among those 7 articles, none re-ported the occurrence of ORN in the maxilla.

Reporting of dental evaluationOf the 22 articles selected, dental evaluation before RTwas reported in 7 articles. Differences in the risk ofdeveloping ORN are shown in Table V.

DISCUSSIONOsteoradionecrosis of the jaws is a well known com-plication of head and neck radiotherapy. It is a uniquetype of radiation late toxicity in the sense that its risk ofoccurrence is dependent not only on the extent ofradiation damage to bone but also on the dental healthof the patient. It is known that the risk of developingORN is increased in patients with poor oral healthbecause more traumatic dental events are to be expec-ted.17,42-44 This is further supported by the findings thatedentulous patients are at a lower risk of developingORN.17 The association of radiation damage and oralhealth can also be explained by the observation ofspontaneously occurring ORN and trauma-inducedORN.45-47 Spontaneously occurring ORN is postulatedto be dependent on the extent of radiation exposure,whereas trauma-induced ORN is more dependent ontraumatic dental events.45-48 Patients receiving higherradiation doses would therefore be more likely to de-velop spontaneously occurring ORN, whereas patientsreceiving lower doses would need trauma to the radi-ated tissue to initiate the development of ORN.45 Marxand Johnson observed that most spontaneous presenta-tions of ORN occurred between 6 months and 2 yearsafter RT, whereas the risk of developing trauma-in-duced ORN lasts indefinitely.46 This observation ex-

plains the occurrence of ORN even 10 years after

ORAL MEDICINE OOOO58 Nabil and Samman January 2012

RT.45,49 Because the risk of developing ORN lasts formany years after RT, it is essential when estimating orcomparing data that a sufficient follow-up period isgiven in published reports to provide enough time forvalid results.

For this reason, we set the criteria for acceptance ofstudies into the present review to be �5 years offollow-up or a median/mean follow-up of �3 years.This period of follow-up provides validity by ensuringsufficient time after RT for most ORN to have oc-curred. Longer follow-up might be desirable but maynot be entirely possible, owing to the limitation im-

Table III. Articles excluded after final eligibility asses

Author YearTotal

follow-upORN/totalpatients

Sunders et al.101 2010 10 y —/918*

Rischin et al.102 2010 27 mo 21/853Pointreau et al.103 2009 36 mo 0/213

Zakotnik et al.104 2007 76 mo —/114*

Bourhis et al.105 2006 �6 y —/266*Le et al.106 2006 61 mo 7/62

Bonner et al.107 2006 54 mo —/424*Bensadoun et al.108 2006 2 y 0/163Zhang et al.109 2005 24 mo 0/115Rischin et al.110 2005 2.6 y 4/121Homma et al.111 2004 63 mo 1/119

Garden et al.112 2004 2.6-2.9 y 6/231Bernier et al.113 2004 60 mo —/323*Denis et al.114 2004 5.5 y 1/220Smid et al.115 2003 32.2 mo 3/114Bartelink et al.116 2002 — 5/49Gupta et al.117 2001 �15 y 12/313Staar et al.118 2001 22.3 mo 14/240Aref et al.119 2000 — 11/385Skladowski et al.120 2000 �3 y 2/100Calais et al.121 1999 35 mo 0/220Wendt et al.122 1998 — 7/270Horiot et al.123 1997 4 y 9 mo —/500*Jeremic et al.124 1997 — 3/154Inoue et al.125 1996 22 mo/24 mo 1/29Maciejewski et al.126 1996 �12 mo 2/44Bachaud et al.127 1996 �5 y 1/83Flores et al.128 1996 1 y —/119*

Fu et al.129 1995 2 y 3/70Fu et al.130 1995 6.1 y 9/399van den Bogaert et al.131 1995 — 10/498

Total 123/5065

ORN, Osteoradionecrosis; Y/N, yes or no; RTOG/EORTC, Radiation Tof Cancer Late Radiation Morbidity Scoring Schema; LENT/SOMANCI-CTC, National Cancer Institute Common Toxicity Criteria.*Not included in calculation.

posed by the survival rate of head and neck cancer

patients. This minimum follow-up period was also setto conform with the findings in the literature where it isreported that 90% or more of ORN cases occur withinthe first 3 years after RT.14,15,50,51 Others have foundthat 70%-80% ORN developed within the first 3years.45,52-54 Shorter mean and median times to onset ofORN after RT of �6 months and 13 months, respec-tively, also have been reported.20,55

ORN is defined as an area of exposed devitalizedirradiated bone that fails to heal over a period of 3-6months in the absence of local neoplastic dis-ease.48,54,56-58 In reporting late radiation toxicity, how-

t (n � 31)Criteria of

diagnosing ORN Reason for exclusion

Y/N Duplicate data; exact no. of ORN casesnot reported (only estimated)

RTOG/EORTC Insufficient follow-upRTOG/EORTC Treatment regimen not uniform within

each armNCI-CTC Duplicate data; exact no. of ORN cases

not reportedRTOG/EORTC Exact no. of ORN cases not reportedY/N Treatment regimen not uniform within

each armRTOG/EORTC Exact no. of ORN cases not reportedRTOG/EORTC Insufficient follow-upY/N Insufficient follow-upRTOG/EORTC Insufficient follow-upY/N Treatment regimen not uniform within

each armRTOG/EORTC Insufficient follow-upRTOG/EORTC Exact no. of ORN cases not reportedNCI-CTC Duplicate dataNCI-CTC Insufficient follow-upY/N Follow-up not reportedY/N Accrual period before 1985Y/N Insufficient follow-up; duplicate dataRTOG/EORTC Secondary analysisY/N Duplicate dataY/N Insufficient follow-up; duplicate dataY/N Follow-up not reportedRTOG/EORTC Exact no. of ORN cases not reportedRTOG/EORTC Follow-up not reportedY/N Insufficient follow-up; duplicate dataY/N Insufficient follow-up; duplicate dataY/N Accrual period before 1985Y/N Insufficient follow-up; exact no. of ORN

cases not reportedRTOG/EORTC Insufficient follow-upRTOG/EORTC Accrual period before 1985Y/N Follow-up not reported; accrual period

before 1985

Oncology Group/European Organisation for Research and Treatmentffects of Normal Tissue/Somatic Objective Management Analytic;

smen

%

—

2.50

—

—11.3

—003.30.8

2.6—

0.52.6

10.23.85.82.92.002.6—

2.03.54.51.2—

4.32.32.0

2.43

herapy, Late E

ever, several scoring systems are used to describe the

I.

-41

OOOO ORIGINAL ARTICLEVolume 113, Number 1 Nabil and Samman 59

“event” of ORN. None of these scoring systems con-forms perfectly to the definition. The most commonscoring system used is the RTOG/EORTC Late Radi-ation Morbidity Scoring Scheme, which was introducedin 1984.1 This scoring system is stratified to differentgrades based on signs and symptoms of bone toxicity(Table VIII). Grade 4 of this scoring system includes

Table IV. Articles selected for final analysis

No. Author Year Follow-upTotal

patient

1 Suwinski et al.21 2008 48 mo 2742 Racadot et al.22 2008 106 mo 1033 Cummings et al.23 2007 6. 9 y 3314 Skladowski et al.24 2006 96 mo 905 Fallai et al.25 2006 8.35 y 1126 Semrau et al.26 2006 57.3 mo 2407 Mendenhall et al.27 2005 38 mo 1018 Budach et al.28 2005 5 y 3229 Huguenin et al.29 2004 39.5 mo 211

10 Cooper et al.30 2004 45.9 mo 40911 Denis et al.31 2003 5.5 y 44

12 Corvo et al.32 2001 60 mo 3213 El-Weshi et al.33 2001 55 mo 3414 Ang et al.34 2001 59 mo 18215 Inoue et al.35 2001 78/85 mo 5116 Fu et al.36 2000 41.2 mo 1,02917 Jeremic et al.37 2000 79 mo 13018 Brizel et al.38 1998 41 mo 11619 Eschwege et al.39 1997 5 y 37420 Dische et al.10 1997 6 y 91821 Maor et al.40 1995 3.5 y 13522 Lee et al.41 1995 3.38 y 504

Total 5,742

NPC, Nasopharyngeal carcinoma; other abbreviations as in Table II

Table V. Osteoradionecrosis (ORN) incidence in relatiinvolved, and dental evaluation

Variable Articles

Tumor sitesHead and neck 10, 21-32, 34-41Nasopharynx 33Sinonasal —

TreatmentAdjunctive 21, 22, 30, 34Curative 10, 23-29, 31-33, 35-41

DeliveryEBRT 10, 21, 23-25, 28, 29, 31-33, 36-39,Brachytherapy 35IMRT/3D-CRT —Not clear 22, 26, 27, 30, 34, 40

Mandible/maxillaMandible 21, 22, 24, 25, 27, 31, 35Maxilla —Not reported 10, 23, 26, 28-30, 32-34, 36-41

Dental evaluationReported 22, 23, 26, 30, 31, 34, 36Not reported 10, 21, 24, 25, 27-29, 32, 33, 35, 37

bone necrosis and spontaneous fracture, which fit the

symptoms and description of advanced ORN. Grade 3of the RTOG/EORTC classification, however, is lessdefinitive. While severe bone pain is a symptom ofORN, no mention is made of bone exposure or seques-trum in grade 3. This lack of specificity is likely due tothis classification not being designed specifically forORN of the jaws but rather to report the radiation bone

ORNcases

Criteria ofdiagnosing ORN Cancer location

Curative vs.adjunctive

4 RTOG/EORTC Head and neck Adjunctive2 RTOG/EORTC Head and neck Adjunctive3 RTOG/EORTC Head and neck Curative2 RTOG/EORTC Head and neck Curative0 Y/N Oropharynx Curative

17 Y/N Head and neck Curative4 Y/N Head and neck Curative

18 RTOG/EORTC Head and neck Curative7 RTOG/EORTC Head and neck Curative8 RTOG/EORTC Head and neck Adjunctive1 NCI-CTC and

LENT/SOMAOropharynx Curative

0 Y/N Head and neck Curative0 RTOG/EORTC NPC Curative3 RTOG/EORTC Head and neck Adjunctive2 Y/N Tongue Curative

17 RTOG/EORTC Head and neck Curative7 RTOG/EORTC Head and neck Curative2 Y/N Head and neck Curative0 RTOG/EORTC Head and neck Curative8 Y/N Head and neck Curative4 RTOG/EORTC Head and neck Curative8 RTOG/EORTC Head and neck Curative

117 2.04%

umor site, treatment aims, radiation delivery mode, jaw

Total patients ORN cases %

5,708 117 2.04%34 0 0%0 0 —

968 17 1.76%4,740 100 2.11%

4,521 77 1.70%51 2 3.92%

— — —1,170 38 3.25%

775 15 1.94%— — —

4,967 102 2.05%

2,338 51 2.18%3,404 66 1.94%

s

on to t

41

toxicity for the whole skeletal system. In this review,

6

ORAL MEDICINE OOOO60 Nabil and Samman January 2012

we accepted grades 3 and 4 of RTOG/EORTC as ORN,because their descriptions best fit the signs and symp-toms of ORN. The LENT/SOMA scoring system,

Table VI. The use of chemoradiotherapy (CRT) and o

n

CurativeFallai et al.25 2006 0/39Semrau et al.26 2006 10/113Budach et al.28 2005 10/164Huguenin et al.29 2004 3/105Denis et al.31 2003 1/27Corvo et al.32 2001 0/20Jeremic et al.37 2000 4/65Brizel et al.38 1998 0/56Subtotal 28/589

AdjuntiveRacadot et al.22 2008 0/52Cooper et al.30 2004 6/201Subtotal 6/253

Total 34/842

Table VII. Use of altered fractionation and osteoradio

n

HyperfractionationCummings et al.23 2007 2/169Fu et al.36 2000 7/253Subtotal 9/422

Accelerated fractionation without total dose reduction (curative)Fallai et al.25 2006 0/37Skladowski et al.24 2006 2/50Fu et al.36 2000 6/522Subtotal 8/609

Accelerated fractionation without total dose reduction (adjunctive)Suwinski et al.21 2008 4/137Ang et al.34 2001 1/76Subtotal 5/213

Accelerated fractionation with total dose reductionDische et al.10 1997 2/552Subtotal 2/552

Total 24/179

Table VIII. Late radiation bone toxicity according tothe Radiation Therapy Oncology Group scoring criteriaGrade Bone morbidity

0 None1 Asymptomatic; no growth retardation; reduced bone density2 Moderate pain or tenderness; growth retardation;

irregular bone sclerosis3 Severe pain or tenderness; complete arrest of bone

growth; dense bone sclerosis4 Necrosis; spontaneous fracture5 Death directly related to radiation late effects

which was introduced to replace the RTOG/EORTC

scoring system, is more specific in its description,which is based on subjective and objective signs andsymptoms, management, and radiographic findings(Table IX).3 It also specifies the mandible as one of itscategories of late toxicity. The clearly described symp-toms, clinical signs, and radiographic features allowinterpretation of the severity of bone toxicity. A scoreof 3 or 4 using the LENT/SOMA scale was consideredto be ORN for the purpose of this review. The LENT/SOMA scale, however, is not widely used, as is evidentin the present review, with only 1 article using it (TableIV).31 One further comment regarding the LENT/SOMA scale is that it specifies the mandible but omitsthe maxilla, so ORN in the maxilla would not bereported or would be reported as mandibular ORN,

dionecrosis (ORN) incidencewith CRT ORN with RT only

% n %

0% 0/73 0%8.9% 7/127 5.5%6.1% 8/158 5.1%2.9% 4/106 3.8%3.7% 0/17 0%0% 0/12 0%6.2% 3/65 4.6%0% 2/60 3.3%4.75% 24/618 3.88%

0% 2/51 3.9%3.0% 2/208 1.0%2.37% 4/259 1.54%4.04% 29/877 3.19%

is (ORN) incidenceith alterednated RT ORN with control

% n %

1.2% 1/162 0.6%2.8% 4/254 1.6%2.13% 5/416 1.20%

0% 0/36 0%4.0% 0/40 0%1.2% 4/254 1.6%1.31% 4/330 1.21%

2.9% 0/137 0%1.3% 2/75 2.7%2.35% 2/212 0.94%

0.36% 6/366 1.64%0.36% 6/366 1.64%1.34% 17/1,324 1.28%

steoraORN

necrosORN wfractio

which would cause underreporting of ORN in the max-

ere are

OOOO ORIGINAL ARTICLEVolume 113, Number 1 Nabil and Samman 61

illa and overreporting of ORN in the mandible. Anotherscale that has been used in reporting late bone toxicityis the NCI-CTC scoring system (Table X). The newestversion 4.0 of this scoring system specifies osteonecro-sis of the jaws as a separate category, thus making itspecific but broad enough to include the maxilla.2 Only1 article used the NCI-CTC scoring system in reportinglate toxicity, and grade �1 in this system was acceptedas ORN for the purpose of this review (Table IV).There are also a few articles that reported ORN aspresent or not without a scoring system (Table IV).Though deficient in measuring the severity of ORN,this is nevertheless a simple and flexible way of report-ing ORN. The lack of uniform scoring, however, cancause differences in interpretation of ORN among dif-ferent investigators, thus affecting the reporting rates.

The present systematic review attempted to provideconclusive data on the current risk of developing ORNin the irradiated head and neck population. The selec-tion of only RCTs assures prospectively collected dataand well planned assessment of bone toxicity. Thisprovides a well known advantage over retrospectivedata, which are exposed to bias, inconsistent follow-up,and inorganized late toxicity assessment. Systematicreview of RCTs also allows valid comparison betweendifferent RT modalities. The adoption of systematicreviews ensures a multicentered data collection whichwould allow generalization of the result. We limitedthis review to articles published from 1995 onward andrecruitment of subjects after 1985 to get the current riskof developing ORN with sufficient follow-up period.

Table IX. Late radiation mandibular morbidity accordManagement Analytic scale*

Grade 1

SubjectivePain Occasional and minimal Intermitten

Mastication DifficultyDenture use Loose denTrismus Noted but unmeasurable Preventing

ObjectiveExposed bone �2 cm

Trismus 1-2 cm opManagement

Pain Occasional nonnarcotic Regular no

Exposed bone AntibioticTrismus and mastication Soft diet

AnalyticMandibular radiograph Questionable changes or

noneOsteoporo

osteosclPanograph x-ray/CT

*Instruction: Score the 9 SOM parameters with 1-4 (score � 0 if th

Among 5,742 irradiated head and neck cancer patients

since 1985, ORN occurred in only 117 of them. Thisputs 2 out of 100 irradiated head and neck cancerpatients at risk of developing ORN and shows a declin-ing trend compared with older studies (Table I) but is inagreement with more recent data.59 The declining trendwas also highlighted by Clayman, where he grosslycompared ORN incidence reported in the literaturebefore and after 1968 and noticed a reduction of inci-dence from 11.8% in the earlier period to 5.4% in thelater period.60 He selected 1968 as the comparisonpoint because the use of megavoltage and supervoltagehad by then replaced most orthovoltage machines inoncologic units.60 Coincidentally, the implementationof a systematic dental program for patients undergoinghead and neck irradiation also started during that pe-riod.16,61,62 This combination of advances in RT tech-

the Late Effects of Normal Tissue/Somatic Objective

2 Grade 3 Grade 4

olerable Persistent and intense Refractory andexcruciating

lids Difficulty with soft foodsInability to use dentures

l eating Difficulty eating Inadequate oral intake

�2 cm or limitedsequestration

Fracture

0.5-1 cm opening �0.5 cm opening

tic Regular narcotic Surgical intervention orresection

Debridement, HBO2 ResectionLiquid diet, antibiotics,

muscle relaxant meds.NG tube, gastrostomy

ioluscent)radiodense)

Sequestra Fracture

ment of necrosis progression

no toxicities); total the score and divide by 9.

Table X. Bone toxicity according to the National Can-cer Institute Common Toxicity CriteriaGrade Osteonecrosis of jaw

1 Asymptomatic; clinical or diagnostic observations only;intervention not indicated

2 Symptomatic; medical intervention indicated (e.g., topicalagents); limiting instrumental ADL

3 Severe symptoms; limiting self-care ADL; electiveoperative intervention indicated

4 Life-threatening consequences; urgent interventionindicated

5 Death

ADL, Activities of daily living.

ing to

Grade

t and t

with soturenorma

ening

nnarco

s

sis (raderosis (Assess

n

ologies, better understanding of biologic tissue reac-

ORAL MEDICINE OOOO62 Nabil and Samman January 2012

tion to radiation and better oral health care among theirradiated population are the likely contributing factorsto the sharp decline in ORN incidence seen in recentyears (Figure 2).55,63 Another possible explanation forthe low incidence of ORN seen in the present review isthe inclusion of all head and neck cancer sites. Earlierstudies tended to show a higher incidence of ORNwhen they reported on high-risk cancer locations, suchas the oral cavity.12,13,17 The exclusion of reirradiationsubjects in this review could also be a factor explainingthe low rate of ORN. Further evidence supporting thediminished ORN risk may also be observed in postir-radiation extraction ORN, where the incidence after1990 was also much lower.64

Several factors are associated with increased riskof developing ORN. Some that have been suggestedinclude gender,20 tobacco and alcohol,20,43 tumor siteor stage,20,43,45,47,53 invasion or proximity of tumorto bone,17,20,43,47,53,54 dental health status,17,43 treatmenttype (EBRT, brachytherapy, neutron beam),17,46,48,54 che-moradiotherapy,20,43,46 radiation dose,20,45-47,50,54,55,65,66

trauma to the bone (extraction, denture-related, cancersurgery),20,43,45,46,48,66 and dose rate/fractionation.46,53,54

In the present systematic review of articles reporting out-come of radiation therapy, we aimed to investigate theradiation-related risk factors, including the location oftumor, radiation delivery methods, curative or adjunctivetherapy, different fractionation schedules, and the use ofCRT. The reporting of dental evaluation before RT and

Figure 2. Osteoradionecrosis incidence rate trend.

location of ORN were also investigated.

Risk of ORN for different tumor locationsTumor site is an important factor in predicting ORNrisk. Within the head and neck, oral cavity tumors,especially of the tongue, floor of mouth, alveolar ridge,or retromolar region, are sites with the highest risk ofdeveloping ORN after irradiation, owing to their prox-imity to the mandible.12,20,47,52,67,68 Tumors originatingin the sinonasal or nasopharyngeal areas present ahigher risk for developing ORN in the maxilla.69-71 Theimportance of tumor location as a risk factor can beexplained by the inclusion of the jaws in the field ofradiation. As observed by Glanzmann and Gratz, nocases of ORN were seen in their series when a head andneck tumor located outside the oral cavity, oropharynx,or nasopharynx regions was irradiated.53 This is furthersupported by the findings of Thorn et al., who reportedthat all but 1 of 80 ORN cases in their series occurredinside the radiation field.45 The differences in tumorsite also determine if parts of the jaws are included inthe radiation field.72 An example of this is in nasopha-ryngeal tumors, where most of the radiation dose wouldinclude the posterior maxilla and mandible,69,71-73

whereas in sinonasal tumors the whole maxilla wouldbe included in the irradiation treatment volume.70 Thesignificance of the relationship of tumor locations andradiation field to the occurrence of ORN can be ob-served in earlier studies. Reuther et al., who reviewed aseries of 830 patients of oral cavity, lip, and oropha-ryngeal tumors, noted that only 1 out of 68 ORN cases

developed in the maxilla.20 Madani et al. reviewed 84

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cases of sinonasal tumor and observed only 1 case ofmaxillary ORN and none in the mandible, thus agreeingwith findings by Homma et al. of 5 maxillary and 1mandibular ORN observed in a series of 47 sinonasaltumor patients.70,74 In their series of 1,758 cases ofnasopharyngeal carcinoma, Cheng et al. reported 48and 30 cases of ORN seen in the maxilla and mandible,respectively.71 Based on these findings, it can be pos-tulated that tumors of the oral cavity or oropharyngealregion would result in a higher incidence rate of ORNbecause of the inclusion of the mandible in the radiationfield. Tumors of nasopharyngeal or sinonasal originmay present a lower risk of ORN owing to the maxillabeing more resistant to radiation necrosis and the ex-clusion of most of the mandible from the radiation field.One of the aims of the present systematic review was toconfirm these differences in tumor location effects onthe risk of ORN. However, we could not achieve thisaim, because most studies reported treatment outcomein the head and neck region without further subdividingdata according to specific tumor sites.

Risk of developing ORN when CT agents wereusedChemoradiotherapy (CRT) offers better locoregional con-trol and overall survival5,75 and is also used to eradicatemicrometastases.5,76 It is divided into induction, concom-itant, or adjuvant therapy based on the timing of CT inrelation to the RT.5,77 CRT has been shown to increaseacute toxicity especially mucositis,30,78 but its effect onlate toxicity is less clear.22,26,28-30 Others have found anincrease in late toxicity with the use of CRT.31,79 Whenthey looked specifically at the ORN risk, Glanzmann andGratz found no increased risk of ORN when CT wasadded to the RT regimen.53 Reuther observed earlier oc-currences of ORN when CT was used in combination withRT.20 In the present review, 10 trials compared the use ofCRT with RT alone. Five studies reported worse ORNoutcome when CRT was used compared with 3 when RTalone was used. Two other studies reported no difference.This variable outcome indicates that the addition of CTagents to RT does not appear to increase the risk ofdeveloping ORN.

Risk of developing ORN in curative RT oradjunctive RT with surgeryIt has been suggested that ablative surgery, includingbone resection or osteotomy before radiation is associ-ated with the development of ORN in the residual orhealing bone.17,20,43,45,46,80-82 Marx and Johnson foundthat among 536 ORN cases, 48 of them were consid-ered to be directly caused by the ablative surgery beforeradiation, and Thorn et al. observed that 10% of ORN

in their series were initiated by the tumor surgery.45,46

Specific procedures, such as mandibulotomy and mandi-bulectomy have been considered to cause an increasedrisk of developing ORN after radiation.80,81,83-85 Otherobservations suggested that when more radical surgery onthe bone is performed, ORN will occur sooner.20 In thepresent review, when subjects who received curative RTwere compared with those receiving adjunctive RT, noimportant difference in the risk of developing ORN wasseen. A possible explanation for this finding is that thehigher ORN risk associated with surgical procedures issimilar to that which is associated with the more aggres-sive therapy of curative intent.

Incidence with different delivery techniquesDifferent radiation delivery methods are said to presentdifferent levels of risk for developing ORN of thejaws.17,46,48,52,54,86 Brachytherapy has been implicatedin a higher risk of developing ORN.17,54 It is postulatedthat because of the proximity of the implant source tothe bone, an increased radiation dose is absorbed.86 Theincreased incidence of ORN cases related to brachy-therapy could also be related to the tumor site, becauseit is used frequently in tongue cancer. The use of aspacer has been reported to reduce the risk of develop-ing ORN in such cases.87,88 More recently, advances inthe delivery of RT, such as 3D-CRT or IMRT, haveraised optimism in the probability of reducing the riskof developing ORN.63,89,90 With the use of these mo-dalities, parts of the mandible can be spared, therebyreducing the risk of ORN.63,89 Although IMRT has thepotential to reduce the incidence of ORN by excludingthe mandible from the high-dosage radiation field,IMRT has primarily been assessed in prospective trialsonly for its ability to exclude the parotid gland from theradiation field to reduce xerostomia.7-9,91 This is exem-plified in a multiinstitutional trial by Eisbruch et al., inwhich the primary objective of the trial was to assessthe feasibility of parotid gland sparing with the use ofIMRT.92 With dose constraint to the mandible set to 70Gy, 6% of patients developed ORN in that trial.92

The location of the tumor also plays a part in thepossibility to exclude the mandible from the radiationfield.93 In tumors of the oral cavity, parts of the man-dible would be within the target volume.89 The exclu-sion of the jaws from the radiation field could be betterachieved in tumor locations distant from the jaws, suchas nasopharyngeal carcinoma.72 So far, there have beenno RCTs reporting the bone toxicity outcome of IMRTcompared with other radiation delivery methods. Datasupporting the benefit of IMRT in preventing ORN alsohave been weak, with only retrospective case series show-ing reduced incidence of ORN after IMRT.63,89,93,94 Otherstudies show no reduced risk with the use of IMRT.92,95

Without a control arm, it is difficult to assess the benefit of

ORAL MEDICINE OOOO64 Nabil and Samman January 2012

IMRT in reducing the risk of ORN, owing to the hetero-geneity of RT regimens and other confounding factors.Most RCTs on 3D-CRT or IMRT have reported only theirefficacy in preventing xerostomia.8,9,91,96 It should bepointed out that by preventing xerostomia, the risk ofdeveloping ORN could be indirectly reduced owing to theimprovement of oral health following the preservation ofsaliva production in the mouth.

Difference in risk with different dose rates andtreatment timeAlthough it is known that the associated risk of develop-ing ORN increases with higher RT doses,19,20,45,47,53,54,97

the effects of altered fractionation regimens to ORNrisk is less clear. Conventional RT is usually describedas 1.8-2.0 Gy once daily, 5 days a week, over 4-8weeks.77 Altered fractionation involves modification ofthis delivery schedule and is usually divided into hy-perfractionation and accelerated fractionation. The useof altered fractionation schedules is associated withbetter locoregional control and survival rate.11 In thesealtered fractionation schedules, beside the total dose,other factors, such as dose per fraction and interfractioninterval, could also influence the outcome of late tox-icity.19,53,82 Hyperfractionation involves delivering anincreased total dose and number of fractions withsmaller dose per fraction to enable better tumor controlwhile not increasing the late toxicity associated withincreased doses.77

Data on the effects of hyperfractionation scheduleson ORN risk have been conflicting. Struder et al.98

reported reduced incidence of ORN with the use ofhyperfractionation, agreeing with the conclusion ofGlanzmann and Gratz.53 In contrast, Niewald et al.observed an increased risk with its use, which wasmainly attributed to reduced interfraction interval.82 Inthe present review, 2 trials compared the use of hyper-fractionation with conventional regimens. Both of thosetrials found a slight increase of ORN incidence in thehyperfractionated group, but because of the very min-imal difference in incidence and the inclusion of only 2trials, the effects of confounding factors on this findingcannot be excluded.

Accelerated fractionation is the shortening of treat-ment time in an attempt to prevent tumor repopula-tion.77 There has been suggestion of possible reducedORN risk with its use.98 The present review concludedthat there was no difference in the risk of developingORN with the use of accelerated fractionation withoutdose reduction, based on 2 trials showing reduced in-cidence and 2 others showing an increased risk. Whenaccelerated fractionation with total dose reduction is

used, there is a reduction in ORN incidence compared

with conventional fractionation, a finding that is ex-pected owing to the total dose reduction.

Risk for the mandible and maxillaThis review further supports earlier reports that themandible is at a higher risk of developingORN.18,20,43,45,47,54 The pattern of mandibular bloodsupply has been implicated as the primary reason forthis predilection.45,99 Others suggest that this obser-vation can be attributed to the fact that the mandibleis included in the radiation field more frequently thanthe maxilla.45,55,100 In the present review, only 7 arti-cles provided information on the location of ORN inrelation to the mandible or maxilla. None of the articlesreported the presence of ORN in the maxilla. Besidesthe vulnerability of the mandible, this finding is also inline with the lack of articles on the nasopharynx andsinonasal region in this review. The failure in mosttrials of reporting the location of bone toxicity can beattributed to the use of the RTOG/EORTC toxicityscale in most articles.

Reporting of dental evaluationMore than two-thirds of articles included in the presentreview failed to report dental assessment. The impor-tance of dental evaluation and treatment before radia-tion cannot be overemphasized. Most reported ORNcases developed directly owing to a dental cause, suchas tooth extraction due to dental caries or periodontaldisease.45,46,54 Reporting of dental evaluation is impor-tant to assess the effectiveness and the outcome of suchprotocols in preventing ORN. Detailed reporting of thedental protocol should be included in published studiesso that effective protocols are identified and followed.Recent efforts by the RTOG to specify prophylacticdental care guidelines is a step in the right direc-tion.63,92 In the present review, we noted 7 articles thatreported dental evaluation. None, however, reported itin detail or made reference or mention of the protocoladhered to. When the incidence of ORN in articles thatreported dental evaluation before RT was comparedwith the remaining articles, there was no increase inORN incidence in the nonreporting group.

ConclusionOur results estimate that 2 out of 100 irradiated patientsare at risk of developing ORN. This provides informa-tion on the risk of developing ORN in the largestcollection of irradiated population with uniform selec-tion criteria and prospectively collected data. The lowincidence can possibly be explained by the increase inoral hygiene awareness, better radiation technologies,inclusion of low-risk and high-risk tumor sites, and the

exclusion of reirradiation patients. This risk is a general

OOOO ORIGINAL ARTICLEVolume 113, Number 1 Nabil and Samman 65

estimation for the whole of the head and neck cancerpopulation undergoing irradiation. As with other riskestimation, an increased risk is expected in patientswith known risk factors for ORN, such as poor oralhealth, gender, tobacco/alcohol consumption, etc. Forexample, when a patient undergoes radiotherapy forhead and neck cancer, the general risk is 2%, but therisk would be higher (6.88%) among the subset of thispopulation that undergoes postirradiation tooth extrac-tion.64

It is also assumed that the risk could be higher inspecific tumor sites, such as oral cavity tumors, infor-mation that this systematic review unfortunately failedto provide. Patients receiving adjunctive RT, acceler-ated fractionation, and CRT show no definitive increasein ORN risk. Accelerated fractionation with dose re-duction shows that a lower radiation dose is associatedwith a lower risk for ORN. Hyperfractionation, in con-trast, shows a possible increased risk. On the whole, therisk stratification for this unique late radiation toxicityrisk appears to be dependent not entirely on radiationdamage but also on the influence of external factors,such as gender, tobacco/alcohol use, dental health sta-tus, or trauma to the bone, highlighting ORN risk asbeing of multifactorial etiology. Future research isneeded to confirm the differences in the risk of devel-oping ORN related to tumor location and various radi-ation delivery techniques. The specific effect of prera-diotherapy dental assessment on the risk of developingORN also needs to be clarified.

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Reprint requests:

Professor Nabil SammanOral and Maxillofacial SurgeryPrince Philip Dental Hospital34 Hospital RoadHong Kong

nsamman@hku.hk